Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid

J. Johnson, R. Hunter, R. McElveen, X. H. Qian, B. S. Baliga, B. S. Pace

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Many different classes of drugs induce fetal hemoglobin (HbF) including histone deacetylase (HDAC) inhibitors such as butyrate and trichostatin A. Although these agents induce gamma-globin expression in culture many are ineffective in vivo, therefore research efforts continue to identify clinically useful fetal globin inducers. We and others demonstrated a role for p38 mitogen activated protein kinase (MAPK) in gamma-globin promoter activation by HDAC inhibitors. In this study we determined the ability of scriptaid, a novel HDAC inhibitor, to induce gamma-globin expression via p38 MAPK signaling. Scriptaid induced gamma-globin in K562 cells and human erythroid progenitors. Furthermore the p38-selective inhibitor SB203580 completely reversed the ability of scriptaid to induce HbF. To test the potential efficacy of scriptaid in humans, in vivo studies were completed in beta-YAC transgenic mice where the gamma-gene is completely silenced. Scriptaid induced reticulocytosis and human gamma-globin mRNA synthesis. At a concentration of 1 mg/kg/day given by intraperitoneal injections twice weekly we observed a significant 1.8-fold increase in gamma-globin mRNA transcripts. The potential for scriptaid as a treatment option for sickle cell disease will be discussed.

Original languageEnglish (US)
Pages (from-to)229-238
Number of pages10
JournalCellular and Molecular Biology
Volume51
Issue number2
StatePublished - Sep 5 2005
Externally publishedYes

Keywords

  • Fetal hemoglobin
  • Gamma-globin
  • Histone deacetylase inhibitor
  • Scriptaid
  • p38 MAPK

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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